Device for delivery of useful agent

ABSTRACT

A device for the controlled continuous administration of an active agent to an environment of use is disclosed. The device comprises a body of erodible agent release rate controlling material containing an agent dispersed therethrough; the rate controlling material is a hydrophobic poly(carboxylic acid) having one ionizable carboxylic hydrogen for each 8 to 12 carbon atoms, which material erodes at a controlled and continuous rate over a prolonged period of time in response to the environment by a process of carboxylic hydrogen ionization, thereby releasing the dispersed agent at a controlled rate over a prolonged period of time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our copending U.S. Pat.application Ser. No. 476,246 filed on June 4, 1974 and now abandoned,which application is a continuation-in-part of U.S. Pat. ApplicationSer. No. 318,831 filed on Dec. 27, 1972 and now abandoned. Thisapplication and the earlier applications are assigned to the sameassignee and benefit of their filing dates is claimed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to devices which dispense active agents to anenvironment of use at a controlled and continuous rate over a prolongedperiod of time. In a preferred embodiment, it relates to deliverydevices for the sustained release of an agent to a substantiallyconstant pH environment, such as an agent to a mammalian patient, andthe like.

2. The Prior Art

The use of poly(carboxylic acids) as enteric coatings has been reportedby Lappas and McKeehan at 51 J. Pharm, Sci. 808 (1962), at 54 J. Pharm.Sci. 176 (1965) and at 56 J. Pharm. Sci. 1257 (1967).

As is well known, enteric coatings are special coatings applied toingestible tablets or capsules which prevent release and absorption oftheir contents until the tablets reach the intestines.

The poly(carboxylic acids) are well suited to this application and thewidely varying pH conditions of the gastrointestinal tract. In thehighly acidic stomach (pH 2) poly(carboxylic acids) are presentcompletely as unionized hydrophobic species which are water insolubleand which prevent the release of any enclosed drug. As thepoly(carboxylic acids) move on to the intestine, they are exposed toalkaline conditions (pH of up to 9) in which they ionize to solublehydrophilic species and release the enclosed drug.

With these prior enteric coating teachings, the release of drug ismerely delayed. The release is essentially a pH-dependent step fuction.

There is no release of drug in the acidic stomach; there is release ofall the drug as the encapsulated drug enters the intestine and the pH ofthe environment changes to an alkaline value.

STATEMENT OF THE INVENTION

It has now been found that poly(carboxylic acids) may be used to form adevice giving a controlled and continuous release of an active agentover a prolonged period of time under conditions of essentially constantpH. This is in direct contrast to the teachings of the prior art of theuse of these materials in enteric coated pills which gave a stepfunction release of drug under conditions of changing pH.

In accordance with this invention, a device is provided which permitsthe controlled and continuous administration of active agent to anessentially contant pH environment. Such a device comprises a body oferodible release rate controlling material containing the active agentdispersed therethrough. The release rate controlling material comprisesa hydrophobic poly(carboxylic acid) having an average of one ionizablehydrogen for each 8 to 22 total carbon atoms. These polyacids erode inresponse to the environment of use at a controlled and continuous rateby a process of carboxylic hydrogen ionization. This erosion extendsover a prolonged period of time and causes the dispersed agent to bereleased at a controlled and continuous rate over a prolonged period oftime.

In a preferred embodiment, the invention involves a device fordelivering drugs to a substantially constant pH environment within thebody of a mammalian patient, with the device eroding when placed in thebody in response to the environment.

Such a device comprises a body of the hydrophobic poly)carboxylic acid)having drug dispersed therethrough. When this device is placed in asubstantially contant pH environment within the body of a mammalianpatient, the poly(carboxylic acid) bioerodes by a process of carboxylichydrogen ionization in response to the mammalian environment andgradually releases drug at a controlled and continuous rate over aprolonged period of time.

The invention further makes possible a process for the controlled andcontinuous administration of drugs to a mammalian patient over prolongedperiods of time. This process involves employing the drugs in a certainform, and applying this form to an environment in the mammalian patientwhich is characterized as having an essentially constant pH throughoutthe period of administration of drug. The drug form employed in thisprocess comprises a body of drug release rate controlling hydrophobicpoly(carboxylic acid) having one ionizable carboxylic hydrogen atom foreach 8 to 22 carbon atoms and having the drug dispersed throughout, thatbioerodes in response to the environment.

In another embodiment, the invention provides devices for the localdelivery of drug to the uterus and vagina which devices are of simpleoperation, give a reliable delivery of drug over a prolonged period oftime, and bioerode in the uterus or vagina in response to theenvironment thereof.

The invention also provides devices for the local and systemic deliveryof drug wherein the device is a nasal, anal, buccal, topical, implant,body passageway, or non-reproduction body cavity device for thecontrolled and continuous delivery of drug as the device erodes inresponse to the environment wherein the device is placed for release ofdrug thereto.

The invention also provides for devices for the release of an activeagent to a non-biological environment with the device releasing activeagent at a controlled and continuous rate as the device erodes inresponse to the environment.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a cross sectional view of a device in accord with thisinvention for releasing active agent at a controlled rate over aprolonged period of time.

FIG. 2 is a cross sectional view of a multi-layered device in accordwith the invention which releases active agent at a varying rate.

FIGS. 3 - 7 inclusive are illustrative of the many embodiments thepresent invention may take.

FIG. 3 is a perspective view of a disc-shaped tablet suitable forreleasing drugs perorally or subcutaneously or for releasing otheractive agents to other constant pH environments.

FIG. 4 illustrates in perspective a device of this invention adapted torelease a controlled amount of active agent into a liquid medium.

FIG. 5 is a cross sectional view of a suppository embodying the presentinvention.

FIG. 6 is a partially cut away elevational view of an intrauterinedevice formed of two connecting rings.

FIG. 7 is a partially cut away elevational view of an intrauterinedevice shaped like a "T", adapted to release a controlled amount ofactive agent into the uterus.

FIG. 8 is a partially sectional elevational view of a device of thisinvention adapted for placement in the cervical canal of a pregnantfemale.

FIG. 9 is a graph illustrating the linear release of active agentachieved with devices of this invention.

DETAILED DESCRIPTION OF THE INVENTION

In accord with this invention, agents may be most advantageouslydelivered to the environment of use over a prolonged period of time bybeing incorporated in a body of hydrophobic poly(carboxylic acid) offrom 8 to 22 carbons per ionizable hydrogen. This body slowly erodes inthe environment of use and is incorporated in a device adapted and sizedfor insertion, positioning and placement in the environment of usethroughout the period of agent administration.

The terms "hydrophobic" and "hydrophobicity" broadly refer to theproperty of a substance to not absorb or adsorb appreciable amounts ofwater. As used in this specification and claims, a more precise meaningof these terms is intended; a hydrophobic material is defined as onewhich absorbs or adsorbs water in a maximum amount not exceeding 10% ofits dry weight.

The phrase "active agent" and the term "agents" as used in thisspecification and accompanying claims comprise any compound, or mixtureof compounds, composition of matter or mixture thereof which whendispensed produces a beneficial result for man, animals or theenvironment of use.

As used herein, the phrase "a prolonged period of time" shall havedifferent meanings with respect to the various delivery devices and theenvironment of use to which it is applied. Normally, it will mean a timeperiod of at least one-half hour to 180 days, and it includes one houror higher, up to two years or more.

In accordance with the present invention, there is provided a device forthe controlled continuous dispensing of a predetermined amount of activeagent over a prolonged period of time.

Such a device is shown as device 10 in FIG. 1. In FIG. 1, device 10comprises an active agent 21 dispersed throughout a body 22 ofhydrophobic poly(carboxylic acid). When placed in an environment havinga controlled and essentially constant pH, poly(carboxylic acid) body 22bioerodes concommitantly releasing the active agent which is dispersedtherethrough.

The polyacids employed are characterized as being hydrophobic whenunionized and as having a specified proportion of carboxylic hydrogens.They are substantially impermeable to the passage of agent andbiological fluids and release entrapped agent by an erosion controlprocess, since these poly(acids) gradually erode in the environment,preferably a biological environment, at a controlled rate by a processof carboxylic hydrogen ionization. These poly(acids) and their erosionproducts are nontoxic and non-irritation to biological tissues such asthe endometrium and other uterine and vaginal tissues.

Suitable poly(carboxylic acids) are the hydrophobic poly(acids) whichare represented by the general formula: ##STR1## wherein: the R's areorganic radicals indpendently selected to provide, on average, from 8 to22 total carbon atoms for each carboxylic hydrogen. Variations of thisratio within this range can vary the erosion and active agent releaserates of devices prepared from these polymeric acids. Organic radicalsrepresented by R¹, R², . . . R^(n) may be selected from hydrocarbonradicals and hetero-atom containing organic radicals. Suitable heteroatoms for employment in R¹, R², . . . R^(n) include oxygen, nitrogen,sulfur, and phosphorus as well as other hetero atoms so long as therequired hydrophobicity and carbon to carboxylic hydrogen average ratiois maintained. The value of n and hence the average molecular weight ofthe polymer is not critical and may vary over a wide range. Suitablemolecular weights, for example, range from about 10,000 to about800,000. Materials within this range erode to products which may beeasily and innocuously passed from the environment of use. Preferredmolecular weights are from about 15,000 to about 500,000.

While not wishing to limit the scope of the poly(acids) intended to beemployed in accord with this invention, and while alternative materialsand preparative schemes are set forth in the description of suitablepoly(acids) which follows, practically speaking, the most common andwidely applied method for introducing a carboxylic acid function, aswell as other hetero atom functions, into a polymeric material of thetype employed in this invention, is to proceed through monomers having acarbon skeleton of at least two carbon atoms. These monomers containpolymerizable olefinic carbon-carbon double bonds. At least a portion ofthese monomers will have appended thereto one or more carboxyl radicals,or suitable precursors thereof and optionally also other hetero atomradicals. The polymer is formed by effecting addition of these monomers,one to another, across the polymerizable double bonds. This generalmethod for forming poly(acids) is well known and does not comprise apart of the present invention. This preparative method may be generallyrepresented by the reaction: ##STR2## wherein

A represents hydrogen or a hydrocarbon and ##STR3## represents acarboxyl group (or carboxy group precursor) containing monomer alsocontaining a polymerizable olefinic double bond. Such monomers include,for example, acrylic acid, substituted acrylic acid, maleic acid, maleicanhydride, crotonic acid and the like. ##STR4## represent organicmonomers containing a polymerizable double bond which may be the same ordifferent than ##STR5##

This preparative technique can be employed to prepare poly(carboxylicacids) in accord with General Formula I having hydrocarbon R's either bypolymerizing suitable hydrocarbon substituted olefinically unsaturatedacids such as substituted acrylic acids and crotonic acids or bycopolymerizing olefinically unsaturated acids, such as acrylic acid orhydrocarbon-substituted acrylic acids or the crotonic acids, withunsaturated hydrocarbons. Suitable poly(carboxylic acids) havinghydrocarbon R's prepared by polymerizing substituted acrylic acids maybe represented by the general formula: ##STR6## wherein R.sub.(HC)represents hydrocarbon substitutes averaging from 5 to 15 carbon atomsin size, for example n-pentyl, cyclohexyl, phenyl, n-decyl,2,2-diethyldecyl, combinations of butyl and hexyl, and the like. Suchmaterials may be prepared by polymerizing the corresponding hydrocarbonsubstituted acrylic acid monomers with free radical initiators asdescribed in U.S. Pat. No. 2,904,541 issued Sept. 15, 1959.

Also useful are poly(carboxylic acids) prepared by copolymerizingunsaturated carboxylic acids as acrylic acid (or substituted acylicacid) with a polymerizable hydrocarbon. These acids may be representedby the general formula: ##STR7## wherein R.sub.(HC) is a hydrocarbonradical of up to about 12 carbons or hydrogen; and R.sub.(CP) is acopolymerized hydrocarbon group. The hydrocarbons which may becopolymerized with unsaturated carboxylic acids include terminallyolefinically unsaturated hydrocarbons and olefinically unsaturatedhydrocarbons having a conjugated carbon-carbon double bond. Thus,typical hydrocarbon groups represented by R.sub.(CP) include ethyl,propyl, butyl, isopentyl, and phenylethyl as result when ethylene,propylene, butadiene, isoprene and styrene, respectively, arecopolymerized with unsaturated acids. Such preparations are set forth in10 J. Poly, Sci. 441 (1946 Series) and 10 J. Poly, Sci. 597 (1946Series).

Poly(carboxylic acids) in accord with General Formula I havinghydrocarbon R's may also be prepared by other known techniques, such asfor example by oxidizing terminal methyl groups on suitable hydrocarbonpolymers to carboxyl groups with alkaline permanate as described in Cramand Hammond Organic Chemistry, 2nd Ed., pages 525-6 1964, published byMcGraw Hill, Inc., or by carboxylating olefinically unsaturatedhydrocarbon polymers by contacting them with carbon monoxide, water andoptionally some hydrogen under conditions of elevated temperature andpressure in the presence of stronly acidic catalysts, for example HF,BF₃, H₂ SO₄ and the like.

Poly(carboxylic acids) useful in the devices of the invention andillustrated by General Formula I may suitably incorporate oxygen atomsin their R's. Oxyhydrocarbon R's include ester groups or ether groups,Poly(carboxylic acids) represented by Formula I incorporating estergroups, as R's, are especially suitable in devices of this invention.They may be readily prepared by partially esterifying acid polymers orcopolymers, which are themselves easily obtained. They offer theadvantage of permitting simple variation of the ratio of carbons toionizable coarboxylic hydrocarbons by varying the extent of partialesterification or the esterifying alcohol employed. As a result, easyadjustment of erosion characteristics of the poly(carboxylic acid)product and hence active agent release rate, is obtained.

As an example of this easy control, consider the case of poly(carboxylicacid). Poly(acrylic acid) is available commercially or may be easilyprepared such as by mixing 167 parts of 60% acrylic acid, 232 parts ofwater, 0.50 parts of potassium peroxydisulfate and 0.25 parts ofpotassium metabisulfite and heating the mixture to 60° C. Poly(acrylicacid) per se, however, is not a suitable poly(carboxylic acid) for usein devices of this invention as it is substantially hydrophilic andwater soluble and does not have the carbon to ionizable hydrogen rationecessary to give suitable erosion and active agent releasecharacteristics.

When half the carboxyl groups of poly(acrylic acid) are esterified byreaction with an alkanol such as hexanol, the resulting partial ester ishydrophobic and has a carbon to ionizable hydrogen ratio within therange necessary for materials employed in the devices of this invention(i.e., 12:1). A similarly suitable material would result if two-thirdsof the poly(acrylic acid) carboxyl groups were esterified with ethanol.

This partial esterification technique is of course not limited totreatment of acrylic acids. Any organic lower poly(carboxylic acid) maybe partially esterified when necessary to achieve the requiredhydrophobicity and carbon to acidic hydrogen ratio. Other poly(acids)which often benefit from esterification include homopolymers ofunsaturated lower carboxylic acids such as the lower alkyl acrylicacids, for example methacrylic and ethacrylic acid; crotonic andpropiolic acid; maleic acid and fumaric acid. Polymers of acidprecursors such as poly(maleic anhydride) may be hydrolyzed andpartially esterified as well. Also suitable for esterification are acidsor precursors copolymerized with lower unsaturated hydrocarbons of from2 to 8 carbons such as ethylene, propylene, butadiene, sytrene and thelike, or with lower unsaturated oxyhydrocarbons such as unsaturatedethers of from 3 to 8 carbon atoms. Many of these polymers andcopolymers are available commercially. Others can be prepared by bulk,solution, emulsion or suspension polymerization using free radicalinitiators at 40-100° C, all methods well known in the art. The partialesterification may be conveniently effected by contacting theacid-containing polymers with a controlled quantity of the esterifyingalcohol at elevated temperature, optionally in the presence of an acidicesterification catalyst. Alcohols suitable for partially esterifying theabove-noted poly(acids) include the hydrocarbon alcohols, preferably thealkanols of from about one to about 16 carbon atoms; for example,methanol, ethanol, isopropanol, n-butanol, cyclohexanol, octanol, thedecanols, and n-dodecanol. Combinations of alcohols may also beemployed.

In addition to being included a partially esterified poly(carboxylicacids), as noted above, ether linkages may be included generally in thepolymers employed in this invention; that is, they may be oxyhydrocarbonR's in General Formula I. Ether groups may be incorporated bycopolymerizing an unsaturated carboxylic acid with an unsaturated ether,for example, acrylic acid, maleic acid, crontonic acid and the like withthe vinyl ethers of from about 3 to about 10 carbon atoms such as methylvinyl ether, ethyl vinyl ether, butyl vinyl ether, hexyl vinyl ether,and the like; for example, by the method described in U.S. Pat. No.2,927,911. Because of the small number of carbon atoms in many of theseunsaturated ethers and acids, it may be desirable, to achieve therequired carbon/acid hydrogen ratio, to terpolymerize these materialswith a non-carboxylic hydrogen-containing material, most suitably anunsaturated terpolymerizable unsaturated hydrocarbon of from 2 to 8carbon atoms such as ethylene, butadiene, or styrene. Examples ofterpolymers are presented hereinafter.

The R's of General Formula I, as oxyhydrocarbons, may contain alcohollinkages. The employment of alcohol linkage-containing oxyhydrocarbonsas R's can pose a problem, however, as the alcohol linkages generallydecrease the hydrophobicity of the poly(acid), often to below the extentof hydrophobicity required of poly(acids) for employment in thisinvention. It is usually possible to incorporate up to about 10%, basistotal polymer, of alcohol linkage-containing R's in the poly(acids).

Nitrogen, sulfur and phosphorous atoms may also be incorporated in Rgroups employed in the polymers represented by General Formula I.Nitrogen may be present as cyano groups, amide groups or imide groups.Amine groups are generally not suitable as they can result in internalsalts being formed between the polymerized acid and amine groups. Sulfuratoms may be present as mercaptan or disulfide linkage, whilephosphorous atoms may be present as phosphate linkages.

A preferred group of materials from which to fabricate the dispensingdevices of this invention comprise hydrophobic polymers of an acidselected from acrylic acid, lower alkyl acrylic acids of from 4 to 6carbon atoms per monomeric unit, and maleic acid; either alone orcopolymerized with up to about 2 moles, per mole of a copolymerizableolefinically unsaturated group such as ethylene or lower (1 to 4 carbon)alkyl vinyl ethers wherein from about 20% to 90% of the acid groups havebeen esterified with an alkanol of from 1 to about 10 carbon atoms andwherein the ratio of total carbon atoms to acidic carboxylic hydrogensis in the range of from about 9:1 to about 20:1.

An even more preferred group of poly(carboxylic acids) comprise thehydrophobic partially esterified copolymers of acrylic acid, methacrylicacid or maleic acid with from 0.2 to 1.5 moles, per mole of acid ofethylene or lower (1-4 carbon) alkyl vinyl ether having from about 35%to about 70% of their total carboxylic groups esterified with loweralkanol of from about 3 to about 10 carbon atoms, said copolymers havinga carbon to acidic carboxylic hydrogen ratio of from about 10:1 to about15:1.

A group of poly(carboxylic acids) most preferred for use in accord withthe present invention comprise hydrophobic copolymers of maleic acidwith about one mole, per mole of maleic acid, of ethylene or methylvinyl ether, said copolymer having about half of its total carboxylicgroups esterified with a lower monoalkanol of from 4 to 8 carbon atoms,wherein the carbon to acidic carboxylic hydrogen ratio has a value offrom about 10:1 to about 14:1.

A presently preferred group of poly(carboxylic acids) are terpolymers ofat least one α,β-unsaturated aliphatic acid of 3 to 8 carbons, an alkylester of such α,β-unsaturated aliphatic acids in which said alkyl is of2 to 8 carbon atoms. Typical terpolymers include one acid monomer andtwo ester monomers, two acid monomers and an ester monomer of the acidfunctionality, an acid monomer, an ester monomer of the acidfunctionality and an acid monomer having a lower alkyl group, and thelike. A particularly preferred terpolymer is comprised of 60 to 75 mol %of a lower alkyl acrylate of the formula CH₂ =CH--COOR₉ where R₉ is analkyl of 2 to 8 carbons, from 15 to 30 mol % of an acid of the formulaCH₂ =CR₁₀ --COOH where R₁₀ is an alkyl of 1 to 8 carbons, and from 5 to15 mol % of an acid of the formula CH₂ =CHCOOH, and the like. Aterpolymer included in this preferred group is comprised of 60 to 75 mol% butyl acrylate, 15 to 30 mol % methacrylic acid and 5 to 15 mol %acrylic acid. The terpolymers have a molecular weight range of 10,000 to1,000,000 or higher.

Typical carboxylic acid monomers useful for producing the terpolymer arethe olefinically unsaturated carboxylic acid containing at least oneactivated carbon-to-carbon olefinic double bond, and at least onecarboxyl group, that is, an acid containing an olefinic double bondwhich functions in polymerization because of its presence in the monomermolecule either in the alpha-beta position with respect to the carboxylgroup, such as ##STR8## or as a part of a terminal methylene groupingCH₂ =C<. Olefinically unsaturated acids of this broad class includeacrylic acids such as acrylic acid itself, methacrylic acid, ethacrylicacid, crotonic acid, sorbic acid, cinnamic acid, beta-styryl acrylicacid, hydromuconic acid, itaconic acid, citraconic acid, and the like.As used for the terpolymer herein, the term carboxylic acid includespoly(carboxylic acids) and those acid anhydrides, such as maleicanhydride, wherein the anhydride group is formed by the elimination ofone molecule of water from two carboxyl groups located on the samepoly(carboxylic acid) molecule. The anhydrides have the general formula##STR9## wherein R₁₂ are selected from the group consisting of hydrogen,halogen, cyanogen, hydroxyl, lactam, alkyl and the like. The term alkylas used herein includes the straight and branched chain alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl,2-methyhexyl, heptyl, and the like.

Representative esters suitable for synthesizing the terpolymer includewithout limitation methyl methacrylate, ethyl methacrylate, n-butylmethacrylate, isobutyl methacrylate, t-butyl methacrylate, hexylmethacrylate, lauryl methacrylate, and other acrylates such ascyclohexyl methacrylate, dimethylaminomethacrylate,2-hydroxymethylmethacrylate, and the like. Acrylic esters of the formulaCH₂ =CHCOOR include the n-alkyl esters methyl, ethyl, propyl, butyl,pentyl, hexyl and heptyl, the secondary and branched chain alkyl estersisopropyl, isobutyl, sec-butyl, 2-methylbutyl, 3-methylbutyl,1-ethylpropyl, 1-methylhexyl and the like. Acrylic acid, its esters andother derivatives are commercially available and known to the art inEncyclopedia of Chemical Technology, Kirk-othmer, Vol. 1, pages 285 to313, 1963; Encyclopedia of Polymer Science and Technology, Vol. 1 pages197 to 226 and 246 to 328, 1964; In U.S. Pat. No. 3,137,660, and thelike.

The poly(carboxylic acids) employed in the devices of this invention aresoluble in organic solvents. Accordingly, the poly(acids) may beconveniently formed by film casting techniques. An organic solventedsolution of the poly(acid), optionally containing active agent, isprepared and cast or drawn to a film. The solvent is then evaporated toyield a continuous film of the poly(acid). The devices may then bepunched or cut from this film. Alternatively, the devices may be moldedfrom such a solution.

A wide range of organic solvents may be used for the casting solutions.Wtih poly(carboxylic acid) materials having total carbon to carboxylichydrogen ratios at the lower end of the range specified for thisinvention, such as ratios in the range of from about 8:1 to about 11:1,it is generally preferred to use relatively polar organic solvents, thatis, organic solvents having dielectric constants, as listed in the 51stEdition of the Chemical Rubber Company "Handbook of Chemistry andPhysics" at pages E-62 through E-64 1970, of greater than about 15, forexample, lower alkanols such as methanol, ethanol, the propanols, 1- and2-butanol, lower alkanones such as acetone, diethyl ketone, ethyl methylketone and cyclohexanone and halogenated and nitrogenated solvents suchas 2-cholorethanol, and nitrobenzene. With poly(carboxylic acids) havinghigher ratio of total carbon atoms to ionizable hydrogens, such as fromabout 14:1 to 22:1, it is generally preferred to use less polar organicsolvents, such as those having dielectric constants of less than about15, especially less than about 10, for example, ethers such as diethylether, isopropyl ether and the like, hydrocarbons such as cyclohexane,benzene and toluene, and other low dielectric materials such as ethylacetate. With the intermediate ratio poly(carboxylic acids) either groupof solvents may be used with the alkanols and alkenones generally beingfavored.

The casting and drying are carried out at moderate conditions such as atambient temperature and pressure. Solvent removal may be facilitated bythe use of vacuum or slightly elevated temperatures. However,substantially elevated temperatures, such as about 100° C, for lengthyperiods, such as for several hours, may be deleterious to some agents orpoly(carboxylic acids).

It is often desired to incorporate plasticizers in the poly(carboxylicacid) materials to improve or vary their physical properties, such as tomake them more flexible. Exemplary plasticizers suitable for employmentfor the present purpose are the pharmaceutically acceptable plasticizersconventionally used, such as acetyl tri-n-butyl citrate, epoxidized soybean oil, glycerol monoacetate, polyethylene glycol, propylene glycoldilaurate, decanol, dodecanol, 2-ethyl hexanol, 2,2-butoxyethoxyethanoland the like. The proportion of optional plasticizer used will varywithin broad limits depending upon the characteristics of thepoly(carboxylic acid) involved. In general, from about 0.01 parts toabout 0.2 parts by weight of plasticizer for each part by weight of thepoly(carboxylic acid) can be used. When plasticizers are included in thepoly(carboxylic acid) materials they are most suitably added prior toshaping the final formed structure, such as by dissolving or dispersingthem in the solution from which the form is cast.

Active agent is released from the delivery devices of this invention byerosion of the poly(carboxylic acid) body through which the agent isdispersed. As the body erodes, it releases the dispersed, entrappedagent. The poly(carboxylic acids) from which the bodies of the device ofthis invention are formed, are substantially imperforated andimpermeable to the passage of active agent by diffusion. Hence, the rateof agent release is proporational to the rate of poly(carboxylic acid)erosion. When the rate of erosion is constant, the rate of release ofagent will also be constant, assuming that the dispersion of agentthrough the body is uniform and that the area of the device which iseroding remains constant.

The aforementioned poly(carboxylic acid) erodes at a controlled ratewhen placed in an environment having a substantially constant pH.Environments in which the present devices give very suitable controlledrates of erosion comprise aqueous environments having a pH throughoutthe period of use of the device selected in the range of from about 6.0to about 9.0. To give a smooth erosion and hence smooth release ofagent, the pH should not vary by more than about ± 0.5 pH units over thelife of the device. Preferred environments vary by not more than about ±0.4 pH units and have a median pH in the range of from about 6.5 toabout 8.5. The more alkaline the pH the more rapidly a givenpoly(carboxylic acid) erodes and releases entrapped agent. At pH's morethan about 6.0, the rate of erosion is too slow to be practical, whileat pH's more basic than about 9.0, the rate is uncontrollably fast.

Devices of this invention are useful for delivering all types of activeagents to all sorts of aqueous environments which have the required pHcharacteristics. They find excellent and preferred application in drugdelivery devices. In such applications, they delivery drugs to thoseenvironments within a mammalian patient which exhibit a constant pH inthe range of from about pH 6.0 to about pH 9.0 throughout the period ofuse. Unlike the gastrointestinal tract which presents a variably acidicand basic pH environment, many areas of mammalian bodies haveessentially constant pH's which fall within the desired pH 6 - pH 9range. For example, the rectum has a pH of about 7.5 The pH of blood isnormally constant at about 7.2. In one of the presently preferredembodiments, the aforementioned device uterine erodes at uterine pH of 7to 7.6, usually 7.2 to 7.3 in the substantially constant pH of theuterus. The products of erosion are innocuous to uterine endometrium andsurrounding tissues. When a device in accord with this inventioncarrying drug is applied to any of these body areas, or similar bodyareas, it erodes at a controlled and constant rate over a prolongedperiod of time. The products of this erosion of the device areinnocuously passed from the body. To increase compatibility with thebody, it may be desirable to coat the devices of this invention with anon-interfering material such as a hydrophilic polymer, for examplepolyvinyl alcohol, gelatin, or the like.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1, as already noted, illustrates generically the delivery device 10of this invention. Device 10 comprises drug 21 dispersed throughpoly(acid) body or matrix 22. Drug 21 may assume a variety ofconfigurations in device 10. It may be in the form of liquid or solidparticles, droplets, a colloid, a molecular solution or other form whichis dispersed through body 22. Device 10 is shown sectioned. In theembodiment shown, device 10 is longer than it is wide and thickness isits shortest dimension. Device 10 also can be wider than it is long, orin another embodiment, device 10 is substantially longer than it isthick. A preferred pattern of erosion and release results when thethickness of the device is smaller than either of its other dimensions,preferably the thickness is less than 10% of the length or width. Withsuch a configuration, an essentially constant surface area is presentedthroughout the period of erosion. Since erosion rate and hence agentrelease rate, are proportional to surface area, a constant, or zeroorder, rate of release results. Exemplary shapes of such "zero orderrelease devices" would be an 8 mm disc and a 6 mm by 12 mm ellipsoid,each punched out of 0.4 mm thick drug-containing poly(carboxylic acid)sheet. The mechanism by which active agent is released by thepoly(carboxylic acid) bodied devices of this invention offers distinctadvantages.

In general, when a body of erodible material having active agentdispersed therethrough is placed in an aqueous environment, thefollowing release mechanisms can occur depending upon the nature of theerodible material: If the erodible enclosing material is hydrophilic, itwill absorb aqueous liquid and swell. Agent can then diffuse out throughchannels of absorbed fluids at rates which are often uneven,unpredictable, difficult to control and highly dependent upon thesolubility of the agent in the fluid. If the agent is soluble in thefluids to an extent greater than about 50 parts per million weight,release is rapid and substantially uncontrolled. If the erodibleenclosing material is hydrophobic but porous, it gives similardiffusion-controlled rates, with the same problems. If the enclosingmaterial is hydrophobic and non-porous, as are the certainpoly(carboxylic acids) employed in the present invention, the rate ofagent release is controlled by the rate at which the enclosing material(matrix 21 in FIG. 1) is eroded or solubilized and enclosed agent (22 inFIG. 1) is uncovered. Such a mechanism offers the advantages of beingmore easily controlled and of providing a more uniform rate of drugrelease.

The poly(carboxylic acids) employed in the devices of this inventionhave proven especially advantageous for erosion-controlled release ofdrugs to the body. Without intent to limit the scope of this inventionby theoretical considerations, it is believed that the uniform andcontrollable rates of erosion observed with devices comprisinghydrophobic poly(carboxylic acids) having an average of 8 to 22 carbonsfor each ionizable acidic-carboxylic hydrogen are the result ofequilibriums inherent in the erosion of these poly(carboxylic acids).

As shown in General Formula I, the poly(carboxylic acids) of thisinvention may be represented as: ##STR10## The carboxyl groups are weakacids which, in their unionized form, are hydrophobic. When placed in anaqueous fluid, a portion of the carboxyl groups ionize to yieldhydrophilic ##STR11## groups and hydronium ions (H₃ O⁺ ). As more of thecarboxyl groups in an initially hydrophobic polymer chain ionize, thechain assumes an increasingly hydrophilic character and eventually goesinto solution in the fluid. This solubilization by ionization occursonly on the outer surfaces of the poly(carboxylic acid) bodies. Even ifminor amounts of fluid do penetrate the surface of the bodies,insignificant ionization can occur there since the inner carboxylgroups, being surrounded by an essentially organic medium exhibit a farhigher pKa than do the carboxyl groups on the surface, which are in amore aqueous medium.

The bioerosion by surface ionization is a reversible reaction, theequilibrium of which is highly sensitive to pH, and thus, oftenself-limiting. As hydronium ions are generated, they tend to clusterabout the polymer body from which they were generated, lower the pH inthe area of the body, and prevent further solubilization by ionization.Some of the clustered hydronium ions gradually disperse or are consumedby alkalinity of the fluid and are replenished via further ionization.The overall erosion rate which results with the poly(carboxylic acids)of this invention is surprisingly slow, perfectly suited for employmentin erodible devices such as device 10 designed to release agents overprolonged periods such as periods of from about 1-2 hours to about 60days. To operate effectively, there must be some removal of hydroniumions, such as the addition of fresh fluid or of base or by means of abuffer.

The self-limiting pH control inherent with these certain poly(carboxylicacids) offers the further advantage of preventing the pH of the fluid ofuse from dropping, by reason of excess hydronium ion release, to a levelwhich would be irritating or corrosive.

The exact rate of erosion is in part dependent upon the chemical makeupof the poly(carboxylic acid). The more hydrophobic the poly(acid) is,the greater the number of ionized carboxyl groups necessary tosolubilize it and the slower its erosion rate. Thus, by changing thehydrophobicity of the certain poly(acids), as may be done by varyingtheir ratio of total carbons to ionizable hydrogens within the range inaccord with this invention, the rate of erosion may be controlled.

FIG. 2 illustrates, by reference numeral 20, an embodiment of thisinvention with which a variable rate of agent release may be achieved.Device 20 is comprised of a series of three concentric layers. The outerlayer comprises a matrix 22 of ionizable hydrophobic poly(carboxylicacid) of this invention that can release agent 21 at a controlled rateover a prolonged period, in the same manner that the matrix in device 10released agent. When the outer layer comprising matrix 22 and agent 21has eroded away, middle layer 31 is exposed, and begins to erode. Layer31 is formed from a bioerodible material, very suitably either the sameor different hydrophobic poly(carboxylic acid) employed in matrix 22.Layer 31, as illustrated contains no agent, and thus during the erosionprovides a period where no drug would be released. When layer 31 hasbeen eroded, the innermost layer is exposed comprising ionizablehydrophobic poly(carboxylic acid) matrix 22a that has particles of agent21a dispersed therethrough. As matrix 22a erodes, agent 21a is releasedat a controlled rate for a prolonged period of time. Many variations ofdevice 20 will be apparent. For example, a greater number of layers maybe employed, a variety of agents or concentrations may be employed inthe several layers, or poly(acids) having different erosion rates may beused in different layers.

FIG. 3 illustrates in cut-away perspective view, by reference, numeral30, a disc-shaped device in accord with this invention. Device 30comprises particles of agent (drug) 21, dispersed throughout body 22 ofpoly(carboxylic acid). As body 22 erodes, agent 21 is released.

A device of such shape could find application as an agriculturaladditive for slowly releasing a variety of active agents such asbiocides, fertilizers and the like to constant pH irrigation fluids. Adevice of such shape might also find application as a depot for drugs.For example, it could be placed in the sac of the eye, thereto releaseocular drugs at a controlled rate for a prolonged period of time.

FIG. 4 illustrates in cut-away perspective view by reference numeral 40an embodiment of this invention suitable for releasing an active agentto an aqueous environment of constant pH. Device 40 comprises activeagent 21 dispersed through body 22 of poly(carboxylic acid). Saidmaterial is enclosed within net container 32 having ring 33 on its topsurface and leads 34 attached to ring 33. Device 40 could be placed, forexample, in a water closet and there attached by means of leads, whereit would release detergent, disinfectant or the like to the watercontained therein. Device 40 might also be affixed in a dishwasher orclothes washer where it would meter, as active agent, wash aids, watersofteners, spot preventors, fabric softeners or the like to the washwater. Similarly, device 40 containing as active agent corrosioninhibitors or lubricants might be placed in an automobile cooling sytemwhere it would dispense such agents over a prolonged period of time.

FIGS. 5, 6 and 7 relate to embodiments of this invention adapted fordelivering drugs to a mammalian patient. FIG. 5 illustrates as 50 asuppository suitable for rectal or vaginal use.

Suppository 50 is rounded at its top end to permit simple, non-painfulinsertion. Suppository 50 comprises drug 21 dispersed throughpoly(carboxylic acid) body 22. When placed in the constant pH vagina orrectum, device 50 erodes and releases drug at a controlled rate over aprolonged period of time.

In FIG. 6 there is depicted an intrauterine drug delivery device 60embodying the invention. Drug delivery device 60 comprises a body ofpoly(carboxylic acid) 22 having particles of drug 21 dispersedtherethrough. Device 60 consists of two continuous loops each having across-sectional diameter of about 1.5 to 2.5 cm. The larger of the twoloops is adapted to be located within the uterine cavity 36 where itcontacts the sides 37 as well as the fundus uteri 38 of the uterus. Thesmaller loop is positioned in the neck of the uterus to assist inmaintaining device 60 within uterine cavity 36. Device 60 slowly erodesin the uterus releasing drug 21 over a prolonged period of time.

FIG. 7 depicts another intrauterine drug delivery device 70 in accordwith the invention. This device is in a "T" configuration, having alateral member or cross bar 41 attached to a depending vertical memberor leg 39 and is adapted to be located within a uterine cavity 36,wherein it optionally contacts sides 37 as well as fundus uteri 38.Device 70 is preferably designed with rounded, non-traumatising ends anda thread 43 attached to the trailing end of member 39, distal from thelead or inserting end of the device, for manually removing device 70from uterus 36. Thread 43 can be any suitable material, or example,nylon surgical thread having a thickness of about 0.002 inches, and thelike. Device 70 is shaped and size adapted to be inserted into uterus 36and be placed and retained there over a prolonged period of time duringwhich drug is delivered. Device 70 is fabricated in another embodimentwith a center core 42 optionally not containing drug in the embodimentshown, but is made of a poly(acid), and an outer layer 22 ofpoly(carboxylic acid) having particles of drug 21 dispersedtherethrough. The thickness of layer 22 is small compared to the area ofdevice 70. Device 70 also can be a solid body 22 of erodible poly(acid)which has drug 21 dispersed throughout. As device 70 erodes, it releasesentrapped drug 21 and delivers it locally to the uterus in which it ispositioned. Drug 21 may be in the form of solid particles, liquiddroplets, colloidal particles, or gels, depending upon the nature of thedrug. As the device erodes, its surface area decreases. This decrease inarea causes the rate of drug release to decrease as well. One way toachieve a more constant rate of drug release is to vary theconcentration of drug within the body of erodible poly(acid) 22,increasing the concentration in the inner areas of device 70 so as tocompensate for the decrease in area. Thus, the area of erosion does notchange substantially during the period or erosion and the rate oferosion remains essentially constant.

FIG. 8 illustrates a device 80 for administering a drug in the cervicalcanal 81. Device 80 is a hollow, cervical tubular body 82 having a pairof openings 83 and a multiplicity of perforations in its walls, notshown, for the passage of cervical fluid through the device.

The devices of this invention may take on a great variety of sizes andshapes. For example, for application and retention in the human uterus,they generally range in size from about 2 cm to about 6 cm in length andwidth. For uterine devices for other animals, larger or smaller sizesmay be used as required for comfort and uterine retention. The devicemay take forms such as cylindrical, bullet, elliptical, circular,bulbous, loop, bow, which lend themselves to intrauterine placement orlodging in the cervix uteri. Specific suitable forms include withoutlimitation, Birnberg's Bow shown in U.S. Pat. No. 3,319,625, the Cometshown in U.S. Pat. No. 3,256,878, the Spring of U.S. Pat. No. 3,397,691,Lippes' Loop, the Ring with Tail, the Ota Ring, and the like. The devicemay also be shaped and size adapted for placement and use in other areasof the mammalian body such as surgical implants and nasal and buccaldevices. The embodiments of the devices of this invention are merelyillustrative and are not to be construed as limiting the scope of theinvention. Other embodiments both for active agent dispensing generally,and drug delivery more specifically, may be employed so long as they areadapted for use in the constant pH environment which this inventionrequires.

The devices of this invention may be used to deliver controlled flows ofany active agent, as the materials have been heretofore described.Preferably, they are employed to deliver drugs. The term "active agent"includes those agents or substances that produce a predeterminedbeneficial and useful result. The active agents include pesticides,germicides, biocides, algicides, herbicides, rodenticides, fungicides,insecticides, anti-oxidants, plant growth promoters, plant growthinhibitors, preservating agents, surfactants, disinfectants,sterilization agents, catalysts, chemical reactants, fermentationagents, cosmetics, foods, nutrients, food supplements, drugs, vitamins,sex sterilants, fertility inhibitors, fertility promoters, airpurifiers, micro-organism attenuators, and other like agents thatbenefit man, animals or the environment.

Devices of this invention are especially useful for delivering all typesof drugs. In the specification and accompanying claims, the term "drug"broadly includes physiologically or pharmacologically active substancesfor producing effects in mammals, including humans, valuable domestichousehold, sport or farm animals such as horses, dogs, cats, cattle,sheep and the like; or laboratory animals such as mice, monkeys, rats,guinea pigs, and the like. While the devices of the invention operatewith special effectiveness with drugs which have a locallized effect,systemically active drugs which act at a point remote from the place ofthe device, may be administered as well, and they are included withinthe term "drugs". Thus, drugs that can be administered by the device ofthe invention include, without limitation: drigs acting on the centralnervous system such as, hypnotics and sedatives such as pentobarbitalsodium, phenobarbital, secobarbital, thiopental, etc.; heterocyclichypnotics such as dioxopiperidines, and glutarimides; hypnotics andsedatives such as amides and ureas exemplified by diethylisovaleramideand α-bromo-isovaleryl urea and the like; hypnotics and sedativealcohols such as carbomal, naphthoxy-ethanol, methylparaphenol and thelike; psychic energizers such as isocarboxyazid, nialamide, phenelzine,imipramine, tranylcypromine, pargylene, and the like; tranquilizers suchas chloropromazine, promazine, fluphenazine, reserpine, deserpidine,meprobamate, benzodiazepines such as chlordiazepoxide and the like; theanticonvulsants primidone, diphenylhydantoin, enitabas, ethotoin,pheneturide, ethosuximide and the like; muscle relaxants andanti-parkinson agents such as mephenesin, methocarbomal,trihexylphenidyl, biperiden, levo-dopa, also known as L-dopa andL-β-3-4-dihydroxyphenylalanine, and the like; analgesics such asmorphine, codeine, meperidine, malorphine, and the like; anti-pyreticsand anti-inflammatory agents such as asprin, salicylamide, sodiumsalicylamide and the like; local anesthetics such as procaine,lidocaine, naepaine, piperocaine, tetracaine, dibucaine and the like;antispasmodics and anti-ulcer agents such as atropine, scopolamine,methscopolamine oxypenonium, papaverine; anti-microbials such aspenicillin, tetracycline, oxytetracycline, chlorotetracycline,chlorampehnicol, sulfonamides and the like; antimalarials such as4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal agentssuch as prednisolone, cortisone, cortisol and triamcinolone;sympathomimetic drugs such as epinephrine, amphetamine, ephedrine,norephineprine and the like; cardiovascular drugs, for example,procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate,mannitol nitrate and the like; diuretrics, for example, chlorothiazide,flumethiazide and the like; antiparasitic agents such as bepheniumhydroxynaphthoate and dichloropehn, dapsone and the like; neoplasticagents such as mechloroethamine, uracil mustard, 5-fluorouracil,6-thioguanine, procarbazine and the like; hypoglycemic drugs such asinsulins, protamine zinc insulin suspension, globin zinc insulin,isophane insulin suspension, and other art known extended insulinsuspensions, sulfonylureas such as tolbutamide, acetohexamide,tolazamide, and chlorpropamide, the biguanides and the like; nutritionalagents such as enitabas, vitamins, essential amino acids, essential fatsand the like; and other physiologically or pharmacologically activeagents.

The devices of this invention deliver with special efficiencyprogestational substances that have antifertility properties andestrogenic substances that have antifertility properties. Thesesubstances can be of natural or synthetic origin. They generally possessa cyclopentanophenanthrene nucleous. The term "progestational substance"as used herein embraces "progestogen" which term is used in thepharmaceutically acceptable steroid art to generically describe steroidspossessing progestational activity, and the former also includes"progestins", a term widely used for synthetic steroids that haveprogestational effects. The active antifertility progestational agentsthat can be used to produce the desired effects in mammals, includinghumans, include without limitation: pregn-4-ene-3,20-dione, also knownas progesterone; 19-nor-pregn-4-en3,20-dione;17-hydroxy-19-nor-17α-pregn-5(10)-3-en-20-yn-3-one; dl-11βethyl-17α-ethynyl-17β-hydroxypregn-4-en-3-one;17α-ethynyl-17-hydroxy5(10)-estren-3-one; 17α-ethynyl-19-norestosterone;6-chloro-17-hydroxypregn-4,6-diene-3,20-dione;17α-hydroxy-6α-methyl-17-(1-propynyl)androst4-en-3-one;9β,10α-pregna-4,6-diene-3,20-dione;17-hydroxy-17α-pregn-4-en-20-yn-3-one;19-nor-17α-pregn-4-en-20yne-3β,17-diol; 17-hydroxypregn-4-en-3,20-dione;17α-hydroxy-progesterone; 17-hydroxy-6α-methylpregn-4-ene-3,10-dione;mixtures thereof and the like.

The estrogenic antifertility agents useful herein also include thecompounds known as estrogens and the metabolic products thereof thatpossess antifertility properties or that are converted to activeantifertility agents in the uterine environment. Exemplary estrogeniccompounds include β-estradiol, β-estradiol 3-benzoate;17-β-cyclopentanepropionate estradiol; 1,3,5(10)-estratriene-3,17β-dioldipropionate; estra-1,3,5(10)-triene-3,17-β-diol valerate; estrone;ethinyl estradiol; 17-ethinyl estradiol-3 methyl ether; 17-ethinylestradiol-3-cyclopentoether; estriol; mixtures thereof and the like.

Another group of drugs which may be delivered with high efficiency bythe devices of this invention include drugs for inducing uterinecontractions such as the oxytocic agents, for example, oxytocin, ergotalkaloids such as ergonovine and methylergonomine, quinine, quinidine,histamine and sparteine.

Yet another group of drugs preferred for delivery from the devices ofthis invention are the prostaglandins. Prostaglandins have a wide rangeof biological activities. Prostaglandins occur as natural body humoralagents are produced synthetically. Such compounds contain an oxygenatedcyclopentane nucleus to which two side chains are attached in thevicinal positions. The hypothetical completely saturated andunsubstituted parent compound of the prostaglandins is called prostanoicacid nd is represented by the structural formula: ##STR12## Nomenclatureof the prostaglandins is derived from the above formula and numberingsystem. Therefore, the structure of the prostaglandin nucleus and sidechains can be described according to the structure of prostanoic acidshown in Formula I. It has been found that four types of prostaglandinnuclei are present in prostaglandins, which gives rise to four series ofprostaglandins commonly designated as E, F, A, and B, which are shown inFormula II - IV inclusive. In structural formulae II - V, a dotted linerepresents a valency bond in the α-configuration and the solid linerepresents a bond in the β-configuration. ##STR13##

Among naturally occurring prostaglandins, two side chains have beendescribed. One contains a terminal carboxylic acid group and may alsocontain a double bond, while the other contains a hydroxyl functionalgroup together with one or two double bonds. These side chains arepresent in natural prostaglandins in three combinations designated 1, 2,and 3, depending upon the total number of double bonds present, so thatthe natural prostaglandins are designated as E₁, E₂, E₃, F₁, F₂, etc.These specific side chains are as follows:

    __________________________________________________________________________    Prostaglandins                                                                        R.sub.1       R.sub.2                                                 __________________________________________________________________________    E.sub.1 F.sub.1 A.sub.1 B.sub.1                                                     (CH.sub.2).sub.6COOH                                                                        CH:CHCH (OH) (CH.sub.2).sub.4 CH.sub.3                    E.sub.2 F.sub.2 A.sub.2 B.sub.2                                                     CH.sub.2 CH:CH(CH.sub.2).sub.3 COOH                                                         CH:CHCH (OH) (CH.sub.2).sub.4 CH.sub.3                    E.sub.3 F.sub.3 A.sub.3 B.sub.3                                                     CH.sub.2 CH:CH(CH.sub.2).sub.3 COOH                                                         CH:CHCH (OH)CH.sub.2 CH:CHCH.sub.2                        __________________________________________________________________________

In addition to the foregoing natural compounds, various biologicallyactive substituted prostaglandins and prostaglandin analogues are knownto the art. These include 19-hydroxy prostaglandins, acylprostaglandins, alkoxy prostaglandins, esters or amides of the carboxylgroup in R₁, as well as prostaglandins having alkyl substituents on theR₁ and R₂ side chains.

While any of the natural and synthetic prostaglandins may be deliveredby the present devices, those of A, E, and F nuclei which have beenshown to be most useful for producing uterine contractions comprise apreferred group for use in these devices, a group herein defined to bethe uterine contraction-inducing prostaglandins. A more preferred groupof prostaglandins comprises those of E₁, E₂, F₁, or F₂ configurations,with from 0 to 2 additional alkyl substituents (preferably methylsubstituents) on chains R₁ and R₂. A most preferred group ofprostaglandins consists of prostaglandin E₁(11α,15(S)-dihydroxy-9-oxo-13-trans-prostenoic acid); prostaglandin E₂(11α,15(S)-dihydroxy-9-oxo-5-cis-13-transprostadienoic acid);prostaglandin F₂.sub.α(9α,11α,15(S)-trihydroxy-5-cis13-trans-prostatrienoic acid); and the15-methyl derivative of prostaglandin F₂.sub.α. Mixtures of the variousprostaglandins, either alone or with added hormonal agents, oxytocin,polypeptides and the like, may be used as well.

The pharmaceutically acceptable, non-toxic salts of the prostaglandinscan also be used including the non-toxic alkali metal and alkaline earthmetal bases such as sodium, potassium, calcium, lithium, copper, andmagnesium hydroxides and carbonates and the ammonium salts andsubstituted ammonium salts, for example, the non-toxic salts oftrialkylamides such as triethylamine, trimethylamine, trisopropylamine,procaine, dibenzylamine, triethanolamine,N-benzyl-beta-phenylethylamine, ethyldimethylamine, benzylamine,N-(lower) alkylpiperdine, N-ethylpiperidine, 2-methylpiperidine andother physiologically acceptable amines and bases.

The above-described prostaglandins are known to the prior art and theyare amply described in references such as Pharmacological Reviews, Vol.20, pages 1 to 48, 1968; Progress In The Chemistry Of Fats And OtherLipids, Vol. IX, pages 231 to 273, 1968; Science, Vol. 157, pages 382 to391; Angewandte Chemie, Vol. 4, pages 410 to 416, 1965; The Journal ofBiological Chemistry, Vol. 238, pages 3555 to 3564, 1963; and otherliterature references.

Representative of other active agents suitable for use with the devicesof this invention include without limitation, insecticides applied toimmature insects, namely daring the embryo, larvae or pupae stage aseffecting metamorphosis and leading to abnormal development, death orthe inability to reproduce. These include aliphatic α,β-unsaturatedesters having a lower alkoxy group which are effective for Hemipteransuch as Lygaeidae, Miridae and Pyrrhocoridae; Lepidopteran such asPyralidae, Noctuidae and Gelechiidae; Coleopteran such as Tenebrionidae,Crysomelidae Plenitabas and Dermestidae; the Dipteran mosquitos andflies; Homopteran such as asphids and other insects. The compounds aredelivered at dosage levels on the order of 0.01 micrograms to 25.0micrograms per insect.

Additional representative agents include cyclopentane insecticides ofthe formula: ##STR14## wherein R₆, R₇, R₁₀, R₈ and R₉ are selected fromthe group consisting of lower alkyl and R₅ is a member selected from thegroup consisting of methyl and ethyl, for use against Lepidoptera,Diptera, Coleoptera and the like. The device can also be used to deliverjuvenile hormones such asmethyl-10,11-(cis)osido-7-ethyl-3,11-dimethyltrideca-2(trans),6(trans)dienoate andmethyl-10,11(cis)oxido-3,7,11-trimethyltrideca-2(trans),6-(trans)-dienoate,and the like.

Other agents which may be delivered by the devices of the inventioninclude herbicides, insecticides, miticides, rodenticides, fungicidesand the like, such as 2,3,5-trichloropyridine-4-ol;4-(methylthio)-3,5-xylyl N-methyl carbamate; O-isopropoxyphenyl N-methylcarbamate; O,O-dimethyl S(N-methylcarbamoyl) methyl phosphorodithioate;2,4-dichlorophenoxyacetic acid; and the like.

The agent is mixed with the bioerodible material and the mixture isfabricated by casting, and the like, into a form suitable for use in theuterus. The erodible material containing drug may be present as theactual intrauterine device or may as well be present as a pendant, flag,or other suitable attachment auxiliary thereto.

The amount of agent employed in devices in accord with this inventionmay vary over a wide range, depending upon the type of agent and thedelivery rate desired and the size and type of device in which the agentis employed. The amount may vary from the minimum effective singledelivery of the agent employed to a maximum amount of agent limited bythe size and/or erosion characteristics of the devices. In general,agent is usually present in an amount equivalent to up to about 90% ofthe weight of the poly(carboxylic acid), although larger or smalleramounts consistant with the above noted general limits may be employedif desired. With the agent loadings of from 0.1 to 40% by weight, basedon the poly(carboxylic acid), or 0.1 to 40% by weight per 100% by weightof the polymer are presently used. For drug delivery devices, the amountof drug present in the device is dependent upon the dosage requirementand the length of time the device is to be placed in the biologicalenvironment. Thus, a single dose of a very potent drug, which may be aslittle as a few micrograms, to an amount sufficient for several hundredor even a thousand doses of a less potent drug, such as up to severalgrams (for example, 5 grams) of drug. In any event, the amount of drugmust be small enough that the erodible material is a continuous phaseand the drug is a dipersed phase therein. In general, drug too ispresent in an amount equal to up to about 90% of the weight ofbioerodible material. Thus, drug loadings of from about 0.01%, based onthe bioerodible material, to about 40% are preferred. That is, for anintrauterine device, 0.01% to 40% by weight per 100% by weight of thepolymer per device is presently preferred.

The devices of this invention are intended to release active agent overprolonged periods of time. For example, the devices release drugslocally to the uterus over prolonged periods of time, that is, forperiods of from about one fourth hour to 30 days or longer. With theprogestational and estrogenic substances, delivery times of from about 1day to 30 days or 2 years or more are preferred, with dosage rates offrom about 5 to 200 mg per day being preferred, thus making it desirableto incorporate at least from about 10 mg to about 6 grams of thesesubstances in a delivery device. When prostaglandins are administeredfor uterine contraction-inducing purposes, it is preferred to administerthe drug over a period of from about 4 hours to about 24 hours at a rateof about 1 microgram/minute to about 25 micrograms/minute. Thus theloading of prostaglandins in the present devices may suitably vary fromabout 250 micrograms up to as much as about 100 milligrams, depending onthe dosage rate and period desired, preferably the loading ofprostaglandin would be between about 1 milligram and about 100milligrams. Similar drug loadings could be determined for the many otherdosage periods and amounts. The intrauterine devices gradually erode inthe uterus and release their drug. The rate of erosion will depend inpart on the recipient's temperature (generally from about 35° C to 38°C), uterine pH (generally pH 7-8) and the amount of uterine fluidspresently available to contact the device.

The rate of erosion and agent release of materials employed in theinvention can be determined experimentally in vitro by testing themunder simulated environmental conditions. For example, the rate oferosion of a device in a moving aqueous stream can be determined byplacing a device in such a stream and repeatedly weighing it todetermine its weight loss. Similarly, the rate of erosion of a materialin a biological fluid such as in tear fluids, as would occur with anocular drug delivery device, may be measured by placing a small weighedsample of the material in a 0.026 M HCO₃ ⁻ solution of pH about 7.4(simulated tear fluids) at body temperature (37° C), agitating for atimed interval, and periodically measuring the amount of material erodedinto the solution. The rate of erosion of a device in uterine fluids, aswould occur with an intrauterine drug delivery device, may be measuredby placing a small weighed sample of the material in physiologicalsaline solution; a solution of pH about 7.4 (simulated uterine fluids)at body temperature (37° C), agitating for a timed interval, andperiodically measuring the amount of material eroded into the solution.To accurately predict in vivo results, it is necessary to multiply thein vitro rates by an experimentally determined constant which takes intoaccount differences in stirring rate and fluid volumes between theliving body and the in vitro test apparatus. This constant may bederived in the cast just set forth by first placing a plurality of smallweighed samples of material in a plurality of environments such as eyesand uterus, and sequentially over a period of time, removing andweighing the samples. The rate thus determined, divided by the rate oferosion observed in vitro with the same material equals the necessaryconstant.

For a more complete understanding of the nature of this invention,reference should be made to the following examples which are givenmerely as further illustrations of the invention, and are not to beconstrued in a limiting sense. All parts are given by weight, unlessstated to the contrary.

DETAILED DESCRIPTION OF EXAMPLES EXAMPLE 1

A device suitable for releasing drug to the essentially constant pHenvironment of the eye employing a hydrophobic poly(carboxylic acid)having on an average from 8 to 22 total carbon atoms for each ionizableacidic carboxylic hydrogen and containing hydrocortisone is prepared inthe following manner:

A. Preparation of poly(carboxylic acid).

12.6 grams (0.10 equivalents) of ethylene-maleic anhydride copolymer(Monsanto EMA, Grade 31) is stirred with 50 ml (0.4 moles) of n-hexylalcohol at 120°-125° C for 7 hours. The solution is cooled to roomtemperature and methylene chloride is gradually added to the cloudpoint. Then more methylene chloride is added to precipitate the product(total vol. 3l). The precipitate is thoroughly leached with themethylene chloride. The solvent is decanted and the product dissolved in75 ml warm acetone. Methylene chloride is added to the cloud point. Thenmore methylene chloride is added to precipitate the product (total vol.2l). The precipitate is then thoroughly leached with the methylenechloride. The solvent is decanted and the product dissolved in 75 mlacetone. The solution is transferred to a polypropylene container andsolvent is removed under vacuum at 50° C to yield the polymer product.The infrared spectrum of the polymer shows broad bands at 1680 and 1780cm.sup.⁻¹ indicative of ester carboxyl. Titration with base shows thatthe hexyl half ester of maleic acid has been formed, and thus the ratioof total carbons to ionizable hydrogens on average is 12:1. A sample ofthe polymer is tested for hydrophobicity by measuring its waterabsorption and is found to pick up only 6% by weight of water.

B. Preparation of hydrocortisone-containing ocular insert.

1.8 grams of the half ester polymer of part A is dissolved in 5 ml ofacetone, with stirring at 25° C. 0.2 grams of micronized hydrocortisoneare dispersed in the solution with stirring. The resulting viscousdispersion is drawn on a polyethylene film to a wet thickness of about0.75 mm. The cast plate is allowed to dry thoroughly to yield a 0.3 mmthick dry film. The resulting film is removed from the polyethylene filmby stripping, and is punch cut into desired shapes and sizes. A 6 mmdiameter circular disc weighs 7 mg and contains 0.7 mg ofhydrocortisone.

C. Testing of inserts.

A series of 0.3 mm thick ocular inserts prepared in part B are eachplaced in 60 ml portions of simulated tear fluids (water containing 0.1moles of K₂ HPO₄ per liter and having a substantially constant pH of7.4) and agitated at 37° C for 40 minutes. Sequentially the ocularinserts are retrieved, dried and weighed. The samples of simulated tearfluids are analyzed by ultraviolet absorption at 248 millimicrons wavelength for hydrocortisone content. The results of these tests indicatethat the inserts erode in this solution of simulated tear fluids in 40minutes at a uniform rate and that the drug release parallels theerosion. The erosion rate in vitro could be decreased almost 2 orders ofmagnitude by decreasing the buffer concentration and the rate ofstirring. The most reproducible results are obtained at the bufferconcentration and rapid stirring rate employed. FIG. 9 illustrates by agraph, drug release rates observed when several series of these insertsare tested in vitro.

A series of these ocular inserts are placed in rabbits' eyes, where theyexhibit a similarly uniform but slower rate of erosion and drug releaseto that observed in the simulated (in vitro) experiments. About 175+hours are required for complete erosion. The factor In vivo/In vitroequals 0.01.

During the in vivo tests, the rabbits are carefully watched for evidenceof ocular irritation. In accordance with the Draize method of measuringocular irritation, the following conditions are watched for: hyperemia,edema and necrosis of the lids; hyperemia, tearing, chemosis andnecrosis of the conjunctiva; exudate from the conjunctiva; follicalhypertrophy; and damage to the cornea or iris. Over the period oftesting these ocular inserts, at worst, mild irritation is noted.

EXAMPLES 2 - 6

The ocular insert preparation of Example 1, parts A and B, is repeated 5times with one variation. The molar excess of n-hexanol employed inExample 1 is replaced with a similar amount of other alkanols asfollows:

    ______________________________________                                               Example      Alkanol                                                   ______________________________________                                               2            n-butanol                                                        3            n-pentanol                                                       4            n-heptanol                                                       5            n-octanol                                                 ______________________________________                                    

The ratio of total carbon atoms to ionizable carboxylic hydrogens ineach of the resulting half esters is as follows:

    ______________________________________                                                        Ratio Carbons                                                 Example         Ionizable Hydrogens                                           ______________________________________                                        2               10                                                            3               11                                                            4               13                                                            5               15                                                            6               16                                                            ______________________________________                                    

Water absorption tests show the products to be increasingly hydrophobic,with the product of Example 2 giving the greatest water pickup with theproduct of Example 6 giving the smallest water pickup.

Erosion tests under the simulated conditions of Part C of Example 1 arecarried out. Constant erosion rates and release rates are noted for eachof the materials. The results of these tests, as well as the in vivoresults which would be predicted for the eye using the factor derived inPart C of Example 1 are as follows:

    ______________________________________                                               Time to Completely                                                                            Time to Completely                                     Example                                                                              Erode In Vitro, Min.                                                                          Erode In Vivo, Hrs.                                    ______________________________________                                        2      10              10-15                                                  3      20              30                                                     4      50              90                                                     5      300             550                                                    6      450             800-900                                                ______________________________________                                    

EXAMPLE 7

A. preparation of polymer.

A mixture of 5 grams of poly(vinyl methyl ether maleic anhydride) 1:1molar ratio copolymer (GAF Corp. Gantrez AM 169) and 30 ml of n-pentylalcohol is stirred at 120° C for 16 hours to yield a viscous product.This product is poured into 500 ml of 2% Na₂ CO₃ solution. The resultingsolution is extracted twice with 400 ml volumes of hexane and acidifiedto pH 1-2 with HCl. The precipitated polymer is collected, washed withslightly acidified water and dried. The product is found to be then-pentyl half ester of maleic acid. The product is hydrophobic,exhibiting an equilibrium water pickup of 9% by weight. It has anaverage 12 carbon atoms for each ionizable carboxylic hydrogen.

B. preparation of drug delivery material.

A 5 gram portion of the half ester product of part A is dissolved in 10grams of acetone with stirring. Micronized progesterone (0.5 grams) isadded to the syrupy ethanol solution of ester. The progesterone does notdissolve in the ester solution but forms a uniform suspension. Thesuspension is cast to a wet thickness of 1.0 mm on silicone releasepaper. The film is dried in moist air at 25° C for72 hours and strippedfrom the release paper as a cloudy film having a final dry thickness of0.3 mm. Although the film is somewhat brittle, it is easily punch cutinto a variety of shapes suitable for insertion in the uterus.

C. testing of material.

A 20 mm by 5 mm strip of this film (30 mg) is attached to a Lippes Loopintrauterine device and inserted into the uterus of an adult humanfemale of 40 to 80 hg. wt. The drug delivery material erodes over aperiod of 30 days releasing about 100 mg of progesterone per day.

EXAMPLE 8

A. preparation of N-butyl acrylate-methacrylic acid copolymer.

A solution of 288 ml (2.0 mole) of n-butyl acrylate, 85.1 ml (1.0 mole)of methacrylic acid, 0.10 g of benzoyl peroxide, and 1000 ml of ethanolis stirred under nitrogen at 50°-53° C for 27 hours. The product isisolated by precipitation into petroleum ether and triturated with ethylether.

B. preparation of inserts.

In a stirred flask were mixed the polymer product of part A 20% ofsodium dodecyl benzene sulfonate surfactant, 10% of benzalkoniumchloride disinfectant and 2% of water soluble green dye. The mixture iscast into 10 gram pellets. When one of these pellets is placed in thewater closet of a standard toilet, it releases dye, disinfectant andsurfactant to the constant pH water in the water closet over a prolongedperiod of time, in a manner characterized by being a continuous andprolonged release.

EXAMPLES 9-10

Two 25.2 gram portions of ethylene maleic anhydride copolymer (monsantoEMA, Grade 31) are each dissolved in acetone. To one portion is added 20grams of water and the mixture is warmed for four hours to yield a fullyhydrolyzed ethylene maleic acid copolymer having a carboxylichydrogen/total carbon ratio of 3. To the other portion is added 7.35grams of absolute ethanol. The mixture is refluxed for 10 hours. Water(20 mls) is added and the mixture is warmed for 4 hours. Titrationanaylsis indicates that 80% of the original maleic anhydride groups arepresent in the form of ethyl half esters while the remaining 20% arepresent as maleic acid. Thus the carboxylic hydrogen/total carbon ratiois about 7. Prior to preparing agent-containing devices of either ofthese materials, films of the polymers themselves are tested in asimulated constant pH environment. Both prove to be substantiallyhydrophilic and to erode essentially uncontrollably.

EXAMPLES 11 - 12

A. preparation of half esters of N-vinyl pyrrolidone-maleic anhydridecopolymers. A mixture of 11.6 g (0.118 mole) of maleic anhydride(Aldrich Chemical Co.), 12.7 ml (0.121 mole) of N-vinyl pyrrolidone(Aldrich Chemical Co.), 0.12 g azodiisobutyronitrile and 140 ml benzeneis stirred under dry nitrogen at 60° C for 42 hours. The mixture iscooled to room temperature and the product 17.3 g (71%) collected byfiltration and characterized as follows: λ KBr max 1680, 1780, 1850cm.sup.⁻¹ ; soluble H₂ O, DMF; insoluble CH₃ OH acetone.

The n-hexyl and n-decyl half esters of the poly N-vinylpyrrolidonemaleic anhydride copolymer are prepared according to theprocedure for the preparation of the n-pentyl half ester of (methylvinyl ether-maleic anhydride) copolymer given in part A of Example 7.Both materials are hydrophobic.

B. production of devices.

Cortisone acetate (12% basis polymer) is added to the polymer and themixture formed into a viscous solution in acetone. This solution is castinto a 1.0 mm thick film which is dried, recovered and punch cut intoshapes suitable for skin patches.

C. testing.

The device of part B is tested in the simulated dermal environment. Then-hexyl half ester erodes and releases agent at a constant rate over a20 minute period. The n-decyl ester device erodes in about 20+ hours.

EXAMPLE 13

A. preparation of n-butyl acrylate-acrylic acid copolymer.

A solution of 14.4 ml (0.10 mole) of n-butyl acrylate, 6.85 ml (0.10mole) of acrylic acid, 0.10 g benzoyl peroxide, and 50 ml ethanol isstirred under nitrogen at 48-52° C for 40 hours. The product is isolatedby precipitation into petroleum ether.

B. insert production.

In acetone, polymer product of part A and 10% of cortisone are blended.The mixture is cast and formed into devices in accord with theprocedures of Example 1, part B.

C. testing of inserts.

The inserts of part B are tested in the simulated ocular environmenttest of Example 1, and found to give a uniform rate of erosion and drugrelease, eroding over a period of 15 minutes.

EXAMPLE 14

A. preparation of polymer.

100 grams of benzene, 10.4 grams (0.13 mole) of styrene and 10.0 grams(0.10 mole) of maleic anhydride are stirred in the presence of 0.1 gramsof bis-azodiisobutyronitrile at 70° C over night. The mixture is cooledand the product is separated by filtration and washed. Characterizationand analysis shows that it is the 1:1 mole ratio copolymer of styreneand maleic anhydride. 10 grams of this polymer is refluxed in ethanolfor 10 hours to yield a viscous product. Analysis shows the product tobe the ethyl half ester of styrene-maleic acid copolymer, a productwhich is hydrophobic and has an average of 14 carbon atoms for eachionizable acidic carboxylic hydrogen.

B. preparation of implant.

10% by weight hydrocortisone implants are prepared by the casting methodof Examples 9-14. Acetone is used as solvent for the casting solution.The finished inserts are 0.5 mm thick.

C. testing of implants. The implants of part B are tested by the methodof Example 1, part C and found to give a linear erosion and drugrelease.

EXAMPLE 15

A. preparation of n-butyl acrylate-acrylic acid-methacrylic acidterpolymer.

A solution of 207.1 g (1.617 mole) of n-butyl acrylate, 21.46 g (0.301mole) acrylic acid, 41.31 g (0.480 mole) methacrylic acid, 1.30 gbenzoyl peroxide and 650 ml of ethanol is stirred under nitrogen at50-53° C for 65 hours. The product is isolated by precipitation into 12liters of hexane and purified by repeated dissolution in approximately600 ml acetone and precipitation into hexane.

B. preparation of insert device.

10% by weight brominated salicylanilide devices are prepared by thecasting method of Examples 9-14. Ethanol is used as solvent for thecasting solution. The finished inserts are 0.5 mm thick.

C. testing of inserts.

The devices of part B are tested by the method of Example 1, part C andfound to give a linear erosion and brominated salicylanilide release.

EXAMPLE 16

A. preparation of n-pentyl acrylate-n-hexyl methacrylate-acrylic acidterpolymer.

A solution of 116.59 g (0.82 mole) of n-pentyl acrylate, 85.12 g (0.50mole) n-hexyl methacrylate, 77.82 g (1.08 mole) acrylic acid, 1.30 gbenzoyl peroxide and 650 ml of ethanol is stirred under nitrogen at50-53° C for 65 hours. The product is isolated by precipitation into 12liters of hexane and purified by repeated dissolution in approximately600 ml acetone and precipitation into hexane.

B. preparation of insecticide releasing device.

10% by weight ethyl 4,4'-dichlorobenzilate devices are prepared by thecasting method of Examples 9-14. Ethanol is used as solvent for thecasting solution. The finished devices are 0.5 mm thick.

C. testing of inserts.

The inserts of part B are testing by the method of Example 1, part C andfound to give a linear erosion and ethyl 4,4'-dichlorobenzilate release.

EXAMPLE 17

A. preparation of a homogenous n-butyl acrylate-acrylic acidmethacrylicacid terpolymer.

The terpolymers prepared as described in Examples 15 and 16 due to thedifferences in reactivity ratios, are compositionally quiteheterogenous. In this example, compositionally homogenous terpolymerscan be prepared using the following procedure: butyl acrylate (62.46 g,0.4875 mole), acrylic acid (7.50 g, 0.104 mole), methacrylic acid (5.80g, 0.0675 mole), 2,2'-azobis(2-methylpropionitrile) (108 mg), andmethanol (425 ml) are placed in a 1 liter 3-neck flask equipped with acondenser, magnetic stirrer, nitrogen line and serum stopper and cooledwith an ice bath. The solution and system are deaerated. A droppingfunnel containing 210 ml deareated methanol is attached to thecondenser. Two 50 cc syringes, colled in a refrigerator, are filled witha deaerated solution composed of the 3 monomers in the molar ratio of67.5:12.5:20 (butyl acrylate, 64.8 g, 0.505 mole, acrylic acid, 6.75 g,0.0938 mole and methacrylic acid, 12.9 g, 0.150 mole).

Delivery of the solution is metered by an infusion pump through a 0.045inch polyethylene tube. A catalyst solution (150 mg of AIBN in 11.8 mlof methanol) is similarly prepared. The reaction mixture is brought toreflux with an oil bath, concommitantly initiating the delivery ofmonomer solution (0.22 ml/min from each of the two syringes) and thedelivery of a catalyst solution (0.077 ml/min). Methanol is added to therefluxing reaction solution in 15 ml increments every 15 minutes. Atotal of 45 ml of monomer feed and 10 ml of catalyst solution is addedduring the 3 hours. The reaction solution is worked up by pouring itinto excess water, drying the precipitate, and re-precipitating theproduct in acetone with hexane.

B. preparation of herbicide devices.

0.5 to 20% by weight of 2,4-dichlorophenoxyacetic acid are prepared bythe casting procedure described above. The finished filled device is0.75 mm thick, and was cut into 1 cm squares. These were placed in ahollow, perforated container for linear erosion and release ofherbicide.

EXAMPLES 18 - 20

To three 10 gram portions of the n-butyl half ester material of Example2 is added respectively 1 g of 1,2-dihydro-pyridazine-3,6-dione; 0.2 9of 2-chloro-4,6-bis(ethylamino)-1,3,5-triazine; and 0.4 g of ametabolite of Gibberella fijikuroi. Each of these is shaped into anelongated device made with the erodible hexyl half ester of Example 1,and dipped into these solutions and dried. 100 mg of material isdeposited. Some devices are dipped into the second and third solutions.Other deposits, such as 500 mg or more can also be deposited. Thedevices release insecticide for about 24 hours, with linear erosionconcommitantly with insecticide release.

EXAMPLE 21

A device suitable for releasing drug to the uterus employing ahydrophobic poly(carboxylic acid) having on an average from 8 to 22total carbon atoms for each ionizable acidic carboxylic hydrogen andcontaining β-estradiol is prepared by using the poly(carboxylic acid)prepared in Example 1. The β-estradiol is added to the intrauterinedevice as follows:

1.8 g of the half ester polymer of part A is dissolved in 5 ml ofacetone, with stirring at 25° C. 0.2 g of crystalline β-estradiol aredispersed in the solution with stirring. The resulting viscousdispersion is drawn on an inert surface to a wet thickness of about 0.75mm. The cast plate is allowed to dry thoroughly to yield a 0.3 mm thickdry film. The resulting film is removed from the surface by stripping. A6 mm × 10 mm strip weighs 15 mg and contains 1.5 mg of β-estradiol. Thedevice was then tested in the following manner:

A 6 mm × 10 mm strip of the material is placed in a 60 ml portion ofsimulated uterine fluid (physiological saline solution having a pH of7.3) and agitated at 37° C for 40 minutes. Periodically, during theagitation the strip is removed, dried and weighed. At the same time, theβ-estradiol content of the simulated uterine fluid is determined bymeasuring the infrared absorption at 225 and 280 millimicrons andcomparing the absorption to a previously preparedconcentration/absorption correlation.

This test shows the uterine device erodes at an essentially constantrate over a period of 40 minutes. Drug release is proportional toerosion. A second device is bonded to an opened ring-shaped intrauterinedevice and inserted in a human uterus. There it erodes over a period of200 hours; the slower erosion being a function of the rate of stirringand the like, releasing β-estradiol locally to the uterus throughoutthis prolonged period. The ratio of In Vivo Rate/In Vitro Rate in thistest is observed to be about 300.

EXAMPLES 22 -26

The preparation set forth in Example 21 is repeated 5 times with onevariation. The molar excess of n-hexanol employed in Example 21 isreplaced with a similar amount of other alkanols as follows:

    ______________________________________                                               Example      Alkanol                                                   ______________________________________                                               22           n-butanol                                                        23           n-pentanol                                                       24           n-heptanol                                                       25           n-octanol                                                 ______________________________________                                    

The ratio of total carbon atoms to ionizable carboxylic hydrogens ineach of the resulting half esters is as follows:

                    Ratio Carbons                                                 Example         Ionizable Hydrogens                                           ______________________________________                                        22              10                                                            23              11                                                            24              13                                                            25              15                                                            26              16                                                            ______________________________________                                    

Water absorption tests show the products to be increasingly hydrophobic,with the product of Example 22 giving the greatest water pick up withthe product of Example 26 giving the smallest water pick up. Erosiontests under the simulated conditions, and release rates, are noted foreach of the materials. The results of these tests, as well as the invivo uterine results which would be predicted are as follows:

    ______________________________________                                               Time to Completely                                                                            Time to Completely                                     Example                                                                              Erode In Vitro, Min.                                                                          Erode In Uterus, Hrs.                                  ______________________________________                                        22     10              30 - 40                                                23     20              90                                                     24     50              270                                                    25     300             1600                                                   26     450             2000 - 2500                                            ______________________________________                                    

EXAMPLE 27

A. preparation of polymer.

A mixture of 5 g of poly(methyl vinyl ether maleic anhydride) 1:1 molarratio copolymer (GAF Corp. Gantrez An 169) and 30 ml of n-pentyl alcoholis stirred at 120° C for 16 hours to yield a viscous product. Thisproduct is poured into 500 ml of 2% Na₂ CO₃ solution. The resultingsolution is extracted twice with 400 ml volumes of hexane and acidifiedto pH 1-2 with HCl. The precipitated polymer is collected, washed withslightly acidified water and dried. The product is found to be then-pentyl half ester of the maleic acid methyl vinyl ether copolymer. Theproduct is hydrophobic, exhibiting an equilibrium water pick up of 9% byweight. It has an average 12 carbon atoms for each ionizable carboxylichydrogen.

B. preparation of uterine delivery material.

A 5 g portion of the half ester is dissolved in 10 g of acetone withstirring. Micronized progesterone (0.5 grams) and 2 g of decanolplasticizer are added to the syrupy ethanol solution of ester. Theprogesterone does not dissolve in the ester solution but forms a uniformsuspension. The suspension is cast to a wet thickness of 0.1 mm onsilicone release paper. The film is dried in moist air at 25° C for 72hours and stripped from the release paper as a cloudly film having afinal dry thickness of 0.3 mm. Although the film is somewhat brittle, itis easily punch cut into a variety of shapes suitable for insertion inthe uterus.

C. assay of material.

A 20 mm ×5 mm strip of this film (30 mg) is attached to a T shapedintrauterine device of a size of about 2 cm across its top bar and about3 cm along its center bar, and inserted into the uterus of an adulthuman female. The drug delivery material erodes over a period of 30 daysreleasing about 100 micrograms of progesterone per day.

EXAMPLES 28 - 30

To three 10 gram portions of the n-butanol half ester material ofExample 22 are added respectively: 1.0 g of the prostaglandin commonlyknown as PGF ₂.sub.α^(') 0.2 g of the prostaglandin known at PGE₂, and0.4 g of PGE₂. Each of these mixtures is dissolved in acetone. Amulti-armed T shaped intrauterine device, made with a bioerodibleflexible center bar and cross arms of the erodible hexy half ester ofExample 21, has the lower end of its center bar repeatedly dipped intothe first of these solutions and dried. 100 mg of ester andprostaglandin is deposited. Second and third multi-armed T devices aredipped into the second and third solution. 100 mg each of these polymerand prostaglandin mixtures are deposited. It would be possible, ofcourse, to deposit more, say 500 mg, or less, say 60 mg, of themixtures.

The three devices are gently inserted into uteri of three firsttrimester pregnant women. The devices release respectively: 10micrograms/minute of PGF₂.sub.α^(') 2 micrograms/minutes of PGE₂, and 4micrograms/ minute of PGE₂, all for periods of about 24 hours. Afteranother 24 to 48 hours, the erodible cross arms begin to drop off andthe devices are expelled. These releases of prostaglandins aresufficient to cause uterine contractions and are suitable for effectingtherapeutic abortion. Varying the concentration of prostaglandin fromabout 1% to about 20% basis polymer would give delivery rates of fromabout 1 μg/minute to about 20 μg/minute.

EXAMPLE 31

An intrauterine device shaped like a triangle is prepared from halfesters of N-vinyl pyrrolidone maleic anhydride copolymers. A mixture of11.6 g (0.118 mole) of maleic anhydride (Aldrich Chemical Co.), 12.7 ml(0.121 mole) of N-vinyl pyrrolidone (Aldrich Chemical Co.), 0.12 gazodiisobutyronitrile and 140 ml benzene is stirred under dry nitrogenat 60° C for 42 hours. The mixture is cooled to room temperature and theproduct 17.3 g (71%) collected by filtration and characterized asfollows:

λ KBr max 1680, 1780 cm.sup.⁻¹ ; soluble H₂ O, DMF; insoluble CH₃ OH,acetone. The n-hexyl and n-decyl half esters of the poly N-vinylpyrrolidone maleic anhydride copolymer are prepared according to theprocedure for the preparation of the n-pentyl half ester of (methylvinyl ether-maleic anhydride) copolymer as previously described. Next,progesterone, 8% based on the weight of the polymer, is added to thepolymer, the mixture formed into a viscous solution in acetone, and castinto a 1.0 mm thick triangle which is dried and used as an intrauterinedevice.

EXAMPLE 32

Preparation of a vaginal device: A solution of 14.4 ml (0.10 mole) ofn-butyl acrylate, 6.85 ml (0.10 mole) of acrylic acid, 0.10 g benzoylperoxide, and 50 ml ethanol is stirred under nitrogen at 48 to 52° C for40 hours. The product is isolated by precipitation into petroleum ether.Next, the polymer and progesterone are blended, cast into an open ringmold shaped and adapted for vaginal placement, and dried. The devicegives a uniform rate of erosion and simultaneously releases progesteroneas erosion occurs.

EXAMPLE 33

An intrauterine device made of a terpolymer of n-butyl acrylateacrylicacid-methacrylic acid is prepared as follows: A solution of 207.1 g(1.617 mole) of n-butyl acrylate, 21.46 g (0.301 mole) acrylic acid,41.31 g (0.480 mole) methacrylic acid, 1.30 g benzoyl peroxide and 650ml of ethanol is stirred under nitrogen at 50 to 53° C for 65 hours. Theproduct is isolated by precipitation into 12 liters of hexane andpurified by repeated dissolution in approximately 600 ml acetone andprecipitation into hexane. Next, 22% by weight of ocytocin is added andthe mixture cast as previously described into uterine devices 25 mm longand 0.5 mm thick. The devices have a linear erosion and linear releaseof drug.

EXAMPLE 34

Precipitation of intrauterine drug releasing device made of n-pentylacrylate-n-hexyl methacrylate-acrylic acid terpolymer. First, a solutionof 116.59 g (0.82 mole) of n-pentyl acrylate, 85.12 g (0.50 mole)n-hexyl methacrylate, 77.82 g (1.08 mole) acrylic acid, 1.30 g benzoylperoxide and 650 ml of ethanol is stirred under nitrogen at 50 to 53° Cto 65 hours. The product is isolated by precipitation into 12 liters ofhexane and purified by repeated dissolution in approximately 600 mlacetone and precipitation into hexane. The polymer is charged withpregn-4-ene-3,20-dione and molded into oval shaped strip for insertioninto the uterus. The device gives a linear erosion and steroid release.

EXAMPLE 35

In this example, an intrauterine device is made from a compositionallyhomogenous terpolymer prepared by using the following procedure: butylacrylate (62.46 g, 0.4875 mole), acrylic acid (7.50 g, 0.104 mole),methacrylic acid (5.80 g, 0.0675 mole), 2,2'-azobic[2-methylpropionitrile] (108 mg), and methanol (425 ml) are placed in a1 liter 3-neck flask equipped with a condenser, magnetic stirrer,nitrogen line and serum stopper and cooled with an ice bath. Thesolution and system are deareated. A dropping funnel containing 210 mldeaerated methanol is attached to the condenser. Two 50 cc syringes,cooled in a refrigerator, are filled with a deaerated solution composedof the 3 monomers in the molar ratio of 67.5:12.5:20 (butyl acrylate64.8 g, 0.505 mole, acrylic acid 6.75 g, 0.0938 mole and methacrylicacid, 12.9 g, 0.150 mole).

Delivery of the solution is metered by an infusion pump through a 0.045inch polyethylene tube. A catalyst solution (150 mg of AlBN in 11.8 mlof methanol) is similarly prepared. The reaction mixture is brought toreflux with an oil bath, concommitantly initiating the delivery ofmonomer solution (0.22 ml/min from each of the two syringes) and thedelivery of a catalyst solution (0.077 ml/min). Methanol is added to therefluxing reaction solution in 15 ml increments every 15 min. A total of45 ml of monomer feed and 10 ml of catalyst solution is added during the3 hours. The reaction solution is worked by pouring it into excesswater, drying the precipitate and re-precipitating the product inacetone with hexane. To a section of the polymer is added 0.5 to 20% byweight of a mixture of estrone and progesterone and molded intointrauterine shaped devices. The device made of the terpolymer is ameans for releasing the drug by linear bioerosion at a uterine pH whenplaced in situ.

EXAMPLES 36 - 45

Repeating the procedures of Examples 1 through 35, agent deliverydevices, sized shaped and adapted for insertion and placement foradministering drug to a mammalian drug receptor site, with the deviceshaving a means for releasing agent concommitantly with the bioerosion ofthe device at mammalian pH are made as described. The devices have aconfiguration and means for maintaining in the corresponding body areaand they are a member selected from the group consisting of a nasaldelivery device, an anal delivery device, an ear delivery device, avaginal delivery device, a topical delivery device, an implant deliverydevice, a device for positioning in a non-reproductive body cavity, anda device for delivering to non-biological environments, and the like.These devices have a wall that is a reservoir for containing the agentand a means for its delivery to the receptor site.

The above examples and disclosures are set forth merely for illustratingthe mode and the manner of the invention as various modifications andembodiments can be made by those skilled in the art, in the light of theinvention without department from the spirit of the invention.

What is claimed is:
 1. A device for the controlled local administrationof drug to the vagina comprising a matrix or hollow body made of drugrelease rate controlling material formed of a hydrophobic poly(acid)represented by the formula: ##STR15## wherein the R's are organicradicals independently selected to provide on the average from 8 to 22total carbon atoms for each carboxylic hydrogen, said body of drugrelease rate controlling material containing a vaginally acceptable drugdispersed therethrough, the device shaped and adapted for insertion andplacement in the vagina, and wherein the release rate controllingmaterial erodes at a controlled rate over a prolonged period of timewhen the device is in the vagina in response to the environment of thevagina, thereby releasing the dispersed drug to the vagina at acontrolled rate over a prolonged period of time.
 2. A vaginal device forthe controlled local administration of a drug to a vagina comprising abody having means shaped and adapted for insertion and placement in thevagina, the body having a wall formed of a drug release rate controllingmaterial comprising a hydrophobic poly(carboxylic acid) having from 8 to22 carbon atoms for each ionizable carboxylic hydrogen, a vaginallyacceptable drug dispersed within the material, and wherein the releaserate material erodes when the device is placed in the vagina, therebyadministering drug at a controlled rate to the vagina over the prolongedperiod of time.
 3. A device for the controlled local administration ofdrug to a vagina comprising a body shaped and adapted for insertion andretention in the vagina, the body having a wall formed of a drug releaserate controlling material comprising a terpolymer consisting of at leastone α,β -unsaturated aliphatic acid in which the alkyl group has 2 to 8carbon atoms, a vaginally acceptable drug dispersed in the material andwherein the device when placed in the vagina the material erodes at acontrolled rate over a prolonged period of time in response to thevaginal environment, thereby dispensing drug to the vagina at acontrolled rate over a prolonged period of time.
 4. The device for thecontrolled administration of drug to the vagina according to claim 1wherein n has a value providing an average molecular weight of from10,000 to 800,000.
 5. The device for the controlled administration ofdrug to the vagina according to claim 1 wherein the drug is anantifertility progestational steroid.
 6. The device for the controlledadministration of drug according to claim 1 wherein the device isring-shaped and adapted for vaginal placement, the poly(acid) is formedof polymerized n-butyl acrylate and acrylic acid, and the drug dispersedtherethrough is progesterone.
 7. The device for the controlledadministration of drug to the vagina according to claim 1 wherein thedrug is a member selected from the group consisting ofpregn-4-ene-3,20-dione; 19-nor-pregn-4-en-3,20-dione;17-hydroxy-19-nor-17 α-pregn-5(10)-3-en-20-yn-3-one; dl-11β-ethyl-17α-ethynyl-17β-hydroxypregn-4-en-3-one; 17 α-ethynyl-17-hyroxy5(10)-estren-3-one; 17 α-ethynyl-19-norestosterone;6-chloro-17-hydroxypregn-4,6-diene-3,20-dione; 17β-hydroxy-6α-methyl-17-(1-propynyl) androst-4-en-3-one; 9β,10α-pregna-4,6-diene-3,20-dione; 17-hydroxy-17 pregan-4-en-20-yn-3-one;19-nor-17 α-pregn-4-en-20-yne-3β,17-diol;17-hydroxypregn-4-en-3,20-dione; 17 α-hydroxy-progesterone and17-hydroxy-6 α-methyl-pregn-4-ene-3,10-dione.
 8. The device for thecontrolled administration of drug to the vagina according to claim 1wherein the drug is an antifertility estrogenic steriod.
 9. The devicefor the controlled administration of drug to the vagina according toclaim 1 wherein the drug is a member selected from the group consistingof β-estradiol; β-estradiol 3-benzoate; 17β-cyclopentane propionateestradiol; 1,3,5(10)-estratriene-3,17β-diol dipropionateestra-1,3,5(10)-triene-3,17-β-diol valerate; estrone; ethinyl estradiol;17-ethinyl estradiol-3 methyl ether; 17-ethinylestradiol-3-cyclopentoether; and estriol.
 10. The vaginal device foradministering drug to the vagina according to claim 2 wherein the drugis a member selected from the group consisting of penicillin,tetracycline, oxytetracycline, chlorotetracycline and chloramphenicol.11. The vaginal device for administering drug to the vagina according toclaim 3 wherein the drug is a member selected from the group consistingof prednisolone, cortisone, cortisol and triamcinolone.
 12. A method forcontrolling fertility which comprises placing in the vagina of a mammala device shaped, sized and adapted for comfortable insertion andplacement in the vagina, said device comprising a matrix made of a drugrelease rate controlling material formed of a hydrophobicpoly(carboxylic acid) having the following formula: ##STR16## whereinthe R's are organic radicals independently selected to provide on theaverage from 8 to 22 total carbon atoms for each carboxylic hydrogen,said matrix containing a vaginally acceptable drug selected from thegroup of antifertility progestational and estrogenic steroids dispersedtherethrough, and wherein the device when positioned in the vaginareleases drug at a controlled rate as the material erodes over aprolonged period of time in response to the environment of the vagina,thereby releasing an effective amount of steroid for controllingfertility in the animal.
 13. A method for controlling fertility whichcomprises placing in the vagina of a mammal a device shaped, sized andadapted for comfortable insertion and placement in the vagina, saiddevice comprising a hollow body formed of a drug release ratecontrolling material made of a hydrophobic poly(carboxylic acid) havingthe following formula: ##STR17## wherein the R's are organic radicalsindependently selected to provide on the average from 8 to 22 totalcarbon atoms for each carboxylic hydrogen, said body containing avaginally acceptable drug selected from the group of antifertilityprogestational and estrogenic steroids contained therein, and whereinthe device when positioned in the vagina releases drug at a controlledrate as the material erodes over a prolonged period of time in responseto the environment of the vagina, thereby releasing an effective amountof steroid for controlling fertility in the animal.